Human Health Risk Assessment - Dealing with Contaminated Sites: From Theory Towards Practical Application - page 249

5.6.3 Physiologically-Based PharmacoKinetic Modelling
With the exception of some medical and occupational data, reliable human data
on health effects related to specific exposure levels are rarely available. Therefore,
as noted previously, potential human health effects are mostly derived from animal
experiments. As a consequence, animal effect data have to be extrapolated to project
data on humans, using assessment factors to accommodate for factors such as the
effects on one population to the other, from short-term high dose to long-term low
dose, etc. Due to lack of scientific knowledge, these extrapolation factors are often
put at 10, 100 or 1000, generally considered as conservative extrapolation factors
(see Section 5.4.3.2 for more details).
In some situations, the prediction of internal exposure or body burden by
use of Physiologically-Based PharmacoKinetic (PBPK) models can provide addi-
tional value. These models focus on a more realistic 'biologically effective dose',
in other words, the exposure which casually relates to effects. A PBPK model
is a tool to estimate the exposure in organs, body tissues or fluids for which
Toxicological Reference Values exist. PBPK models describe the fate and trans-
port of contaminants in the human body, that is, the rate at which contaminants
are adsorbed, distributed, metabolised, excreted (renal excretion) and eliminated
(hepatic elimination). For this purpose, these models seek to mimic the physio-
logical and biochemical processes of the human body, and include equations on
transport in the blood, partitioning into tissues and enzymatic conversion. PBPK
modelling also offers the potential to extrapolate outside the range of experimental
conditions.
PBPK modelling has been used in medicines, for many decades. Its applica-
tion in human health contaminated site management, certainly in regard to formal
regulations, has so far been limited. The poor availability of suitable pharmacoki-
netic models for a variety of contaminants hampers their use in contaminated
sites Risk Assessment. Moreover, enhanced data requirements limit their use,
certainly in lower tier Risk Assessments. Leggett et al. ( 2003 ), as an example,
developed a PBPK model for the purpose of investigating the fate of caesium
in the human body. That model, which was constructed around a detailed blood
flow algorithm, includes the calculation of the transfer of caesium from the blood
plasma into the tissue and vice versa, and the secretions into the gastrointesti-
nal tract. The British 'Risk Assessment and Toxicology Steering Committee'
endeavoured to arrive at a more standardized approach to formal frameworks
(Government/Research Councils Initiative on Risk Assessment and Toxicology
1999 ). Cornelis et al. ( 2006 ), as another example, used the Integrated Exposure
Uptake Biokinetic (IEUBK) model in order to estimate blood lead concentrations of
children exposed to lead in the vicinity of a non-ferrous plant situated in Hoboken,
Belgium.
For larger and more polar contaminants, for which body membranes offer more
resistance to permeation, more insight in the fate and transport processes in the
human body is especially needed. For this purpose, the development of databases
for basic morphological and physiological parameters has been encouraged.